In the crowd I looked for her hundreds of times;
When all at once, as I turned my head,
And quite unexpectedly, I found her there where lantern lights were dim.
Xin Qiji (1140-1207)
In the golden age of drug discovery (ca. 1935-1975), with the help of two magic weapons (chemocentric approaches and phenotypic screening), numerous pioneers made many great discoveries that did so much to extend and enhance human life. Recent research in network pharmacology provides a new strategy known as polypharmacology for treating complex diseases. Magic shotguns (selectively non-selective drugs) are the biggest weapons in polypharmacology’s battle against complex diseases. Now we decide to return to the fundamentals of drug discovery while keeping up with new technologies. We rely on these magic weapons to develop new therapies to treat stroke. Our powerful weapons include: magic shotguns (selectively non-selective drugs), chemocentric approaches, and phenotypic screening.
Polypharmacology: the concept that a molecule is designed to bind to two or more targets simultaneously so that the combined effect has a greater therapeutic outcome than just binding to one target. A multi-targeting drug is much more efficacious due to its cumulative efficacy at all or most of its individual targets making it much more effective in complex and multifactorial diseases, where multiple proteins and pathways are involved in the onset and development of the disease [1].
Magic shotguns: selectively non-selective drugs that interact with several molecular targets. The concept of the magic shotgun does not imply that the goal is to aim at many targets in order to hit the relevant or critical one, but rather that many targets must be hit in order to derive therapeutic benefit [2]. Network theoretical approaches suggest that this strategy may be particularly effective for diseases of complex pathophysiology [3].
Chemocentric approaches: starting a drug discovery program with a biologically active molecule with known pharmacology (lead compound) served as the starting point.
Phenotypic screening: an empirical and observation-based approach that tests compounds directly in a physiologically relevant model system without a prior understanding of the molecular mechanism of drug action.
References
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Kabir A, Muth A. Polypharmacology: The science of multi-targeting molecules. Pharmacol Res. 2022; 176: 106055.
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KROEZE WK and ROTH BL. Polypharmacological Drugs: “Magic Shotguns” for Psychiatric Diseases. In: Peters JU, editor. Polypharmacology in drug discovery. Hoboken, NJ: John Wiley & Sons, Inc, 2012, p135.
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Bianchi MT, Pathmanathan J, Cash SS. From ion channels to complex networks: magic bullet versus magic shotgun approaches to anticonvulsant pharmacotherapy. Med Hypotheses. 2009; 72(3): 297-305.